Clinical characteristics of Campylobacter bacteremia: a multicenter retrospective study

Campylobacter species are the pathogens of the intestinal tract, which infrequently cause bacteremia. To reveal the clinical characteristics of Campylobacter bacteremia, we performed a retrospective, multicenter study. Patients diagnosed with Campylobacter bacteremia in three general hospitals in western Japan between 2011 and 2021 were included in the study. Clinical, microbiological, and prognostic data of the patients were obtained from medical records. We stratified the cases into the gastroenteritis (GE) and fever predominant (FP) types by focusing on the presence of gastrointestinal symptoms. Thirty-nine patients (24 men and 15 women) were included, with a median age of 57 years and bimodal distribution between those in their 20 s and the elderly. The proportion of GE and FP types were 21 (53.8%) and 18 (46.2%), respectively. Comparing these two groups, there was no significant difference in patient backgrounds in terms of sex, age, and underlying diseases. Campylobacter jejuni was exclusively identified in the GE type (19 cases, 90.5%), although other species such as Campylobacter fetus and Campylobacter coli were isolated in the FP type as well. Patients with the FP type underwent intravenous antibiotic therapy more frequently (47.6% vs. 88.9%), and their treatment (median: 5 days vs. 13 days) and hospitalization (median: 7 days vs. 21 days) periods were significantly longer. None of the patients died during the hospitalization. In summary, we found that nearly half of the patients with Campylobacter bacteremia presented with fever as a predominant manifestation without gastroenteritis symptoms.

www.nature.com/scientificreports/ (gastrointestinal manifestations and fever), time from onset to blood culture sampling, pathogenic organisms, laboratory test results on admission (complete blood counts and biochemistry), treatment (intravenous therapy and treatment periods), and prognosis (intensive care unit [ICU] admission rate and hospitalization periods) were extracted from medical records without personally identifiable information. Based on the National Studies of Acute Gastrointestinal Illness' criteria 10 , patients with at least one episode of diarrhea and/or vomiting were defined as "GE (gastroenteritis) type, " while the remaining patients who had no diarrhea or vomiting in their whole episodes were considered "FP (fever predominant) type. " The shock index of each patient was calculated by dividing pulse rate by systolic blood pressure 11 . Clinical and laboratory parameters of the two types were compared.
Blood culture and microbiological identification. Each

Treatment and prognosis.
Thirty-five patients (89.7%) were hospitalized. Three patients (8.6%) were readmitted to other hospitals for rehabilitation and the remaining 32 (91.4%) were discharged to their homes. In total, only two patients (5.1%) were admitted to ICUs for postoperative management of an infected aneurysm and septic shock. Overall, 37 patients (94.9%) were treated with antibiotics and 26 (66.7%) received intravenous therapy. As a complication, infected aneurysm of the iliac artery and subcutaneous soft tissue infection were observed in one and five cases, respectively.

GE type vs. FP type.
Comparisons of the clinical and microbiological characteristics of the patients are provided in Table 1. Among the 39 cases, the number of patients in GE type and FP type was 21 (53.8%) and 18 (46.2%), respectively. Comparing these two types, there was no significant difference in the patients' backgrounds, such as sex, age, and underlying diseases, whereas an exposure history was identified more frequently in the GE type. The shock index was also not significantly different between the two types. In addition to diarrhea and vomiting, stomachache was significantly predominant in the GE type: 15 patients (71.4%) with GE type vs. 2 patients (11.1%) with FP type. Similarly, fever was observed at the time of hospital visit in 20 patients (95.2%) with the GE type and in 15 patients (83.3%) with the FP type. Among 18 FP type patients, three suffered from lower limb cellulitis, two suffered from femoral osteomyelitis, and two suffered from febrile neutropenia associated with lymphoma. Times from the onset to blood culture sampling did not differ between the two types: 1 (IQR: 1-2) days in the GE type and 0 (IQR: 0-2) days in the FP type (P = 0.86). Microbiologically, C. jejuni was exclusively identified in the blood sample of up to 19 patients (90.5%) in the GE type, although other species such as C. fetus and C. coli caused bacteremia in the FP type as well. Comparing the laboratory results, hypokalemia and elevated serum creatinine levels were significantly associated with GE type (Table 2). Patients with the FP type underwent intravenous antibiotic therapy more frequently than those with GE type: 10 (47.6%) vs. 16  www.nature.com/scientificreports/ [6][7][8][9][10][11][12][13][14][15][16][17][18]) than in the GE group (5 days [IQR: 3-10]) ( Table 1). ICU admissions were observed in one case each for the GE and FP types. The median duration of hospitalization was significantly longer in the FP group (21 days ) than in the GE group (7 days [IQR: [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]). Log-rank test analysis also resulted in longer hospitalization in the FP-type (P < 0.01) (Fig. 2). None of the patients died during the hospitalization.

Discussion
In this study, we investigated the clinical and microbiological characteristics of Campylobacter bacteremia in multiple medical centers across Japan. Clinically, our data highlighted that Campylobacter bacteremia inflicts not only the elderly, but also young patients in their twenties. Unlike Salmonella, which is known not only as a causative bacterium of gastroenteritis but also a cause of fever of unknown origin (FUO) 13 14 , in the present study, the highest number of cases was observed in those aged 20-29 years. Consistent with our own results, infected young patients without any particular risk factors developing Campylobacter bacteremia has been reported in recent studies 5,6 . Second, the underlying medical backgrounds of patients with GE-and FP type Campylobacter bacteremia were not significantly different. Although typical campylobacteriosis is accompanied by gastroenteritis symptoms, vulnerable patients with immunocompromising factors are reported to have fewer enteritis symptoms 15 . Another retrospective cohort study also suggested that primary bacteremia without gastroenteritis occurs, especially in immunocompromised patients 8 . However, our patients with GE-and FP type diseases showed similar clinical backgrounds, indicating that patients without particular underlying medical conditions can also present with FUO-like Campylobacter bacteremia. Thus, blood culture sampling remains essential even for previously healthy individuals, to diagnose Campylobacter bacteremia. Considering that blood cultures are not routinely obtained for patients with gastroenteritis in general practice, there may be many more bacteremia patients than are currently recognized 16,17 . Figure 1. Incidence of Campylobacter bacteremia by age group and month. Patient age groups were distributed bimodally between the 20s and the elderly (a). An incidence peak was observed in September (b). Table 2. Comparison of laboratory data on admission between GE type and FP type Campylobacter bacteremia. The data were analyzed by the Mann-Whitney U test. Median and interquartile range are demonstrated. ALT alanine amino transferase, AST aspartate aminotransferase, Cl chloride, Cr creatinine, CRP C-reactive protein, Hgb hemoglobin, K potassium, LDH lactate dehydrogenase, Plt platelets, Na sodium, UN urea nitrogen, WBC white blood cells, GE gastroenteritis, FP fever predominant. www.nature.com/scientificreports/ Laboratory data analysis would not be informative for distinguishing between patients with GE type and FP type Campylobacter bacteremia. Compared with patients with the FP type, those with the GE type showed elevated serum creatinine levels (median; 0.95 mg/dL vs. 0.68 mg/dL). This was reasonable considering that such patients were more dehydrated because of gastroenteritis-associated vomiting and diarrhea. Otherwise, there were no remarkable points to be addressed in routine laboratory data.
The unique features of Campylobacter species should also be considered. C. jejuni is the most common species in human infections and frequently causes gastroenteritis, but fewer complications develop outside the gastrointestinal tract 14,16 . Notably, our data revealed that C. jejuni potentially causes bacteremia and demonstrates a FUO-like presentation as well, which has also been pointed out in the preceding literature 5,6 . Despite being a rare species for human infection, C. fetus is more common in agriculture or livestock with cattle and sheep as the main reservoirs and tends to cause bacteremia without apparent gastroenteritis in humans 18,19 . Thus, the isolation of various Campylobacter species other than C. jejuni in FP type was consistent with previous findings. This finding can be partly attributed to the improvement in bacterial identification in microbiological laboratories 20 .
Previous studies estimated the mortality rate of Campylobacter bacteremia to be 4-28% 5,21 , whereas no hospital deaths were observed in our study. Although details of the direct causes of death in these reports were unavailable and it is difficult to simply compare our cohort with those included in preceding studies, our study also included some patients with complicated, immunocompromised underlying diseases. Delayed appropriate antimicrobial therapy, as a consequence of a lack of clinical symptoms, is reportedly associated with high mortality, defining the prognosis of Campylobacter bacteremia 14,22 . However, the time from onset to diagnosis did not differ between GE and FP types in the present study. Further studies with larger case numbers are needed to clarify this point.
One strength of this study is that we stratified the cases from a clinical perspective based on the presence of symptoms of gastroenteritis. Previous studies on Campylobacter infections have focused on the differences in bacterial species, and our results should thereby provide valuable additional information for clinicians. Nevertheless, this study has some limitations. First, due to the retrospective nature of the study, there were some missing values in clinical and microbiological data. Due to the study design, GE symptoms may have been overlooked in some cases of FP type, which cannot be optimized any further. Second, a selection bias may have existed because only blood culture-positive cases were included. Third, this study could not provide epidemiological data, such as the incidence or prevalence of bacteremia cases among Campylobacter infections. Forth, there may be interviewer bias in examining exposure history in the GE type. Finally, due to the limited number of cases, we could not apply multivariate analysis to identify clinical and microbiological factors to distinguish between ancillary information of the GE and FP types. Despite these limitations, we believe that our study provides additional data for understanding Campylobacter bacteremia.
In conclusion, we revealed the clinical and microbiological characteristics of Campylobacter bacteremia through a multicenter investigation. Nearly half of the patients showed fever-predominant manifestations, and their clinical backgrounds were comparable to those of patients with gastroenteritis symptoms. However, patients with fever-predominant Campylobacter bacteremia require longer treatment and hospitalization periods. Clinicians should recognize that patients with Campylobacter infections can present with fever alone as those with FUO do, even in the absence of conventional GE symptoms.

Data availability
Data in detail will be available if requested to the corresponding author.